Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

ABSTRACT

The invention relates to ophthalmological compositions for topical treatment of glaucoma or ocular hypertension comprising an effective intraocular pressure reducing amount of a prostaglandin derivative of PGA, PGB, PGD, PGE or PGF, in which the omega chain contains a ring structure, in an ophthalmologically compatible carrier. The invention further relates to the preparation of said compositions and their use for treatment of glaucoma or ocular hypertension.

This application is a continuation of application Ser. No. 08/461,341filed on Jun. 5, 1995, which is a divisional of application Ser. No.07/986,943 filed on Dec. 8, 1992 (now U.S. Pat. No. 5,422,368), which isa continuation of Ser. No. 07/469,442 filed on Apr. 10, 1990 (nowabandoned), which is the U.S. National Stage application PCT/SE89/004575 filed Sep. 6, 1989.

The invention is concerned with the use of prostaglandin derivatives ofPGA, PGB, PGD, PGE and PGF, in which the omega chain has been modifiedwith the common feature of containing a ring structure, for thetreatment of glaucoma or ocular hypertension. The invention relates alsoto ophthalmic compositions, containing an active amount of theseprostaglandin derivatives, and the manufacture of such compositions.

Glaucoma is an eye disorder characterized by increased intraocularpressure, excavation of the optic nerve head and gradual loss of thevisual field. An abnormally high intraocular pressure is commonly knownto be detrimental to the eye, and there are clear indications that, inglaucoma patients, this probably is the most important factor causingdegenerative changes in the retina. The pathophysiological mechanism ofopen angle glaucoma is, however, still unknown. Unless treatedsuccessfully glaucoma will lead to blindness sooner or later, its coursetowards that stage is typically slow with progressive loss of thevision.

The intraocular pressure, IOP (abbr. of intraocular pressure) can bedefined as according to the formula:

IOP=P _(e) +F×R  (1)

where P_(e) is the episcleral venous pressure, generally regarded asbeing around 9 mm Hg, F the flow of aqueous humor, and R the resistanceto outflow of aqueous humor through the trabecular meshwork and adjacenttissue into Schlemm's canal.

Besides passing through Schlemm's, canal aqueous humor might also passthrough the ciliary muscle into the suprachoroidal space and finallyleave the eye through sciera. This uveoscleral route has been describedfor instance by Bill (1975). The pressure gradient in this case isinsignificant compared to the gradient over the interior wall ofSchlemm's canal and adjacent tissue in the former case. The flowlimiting step along the uveoscleral route is assumed to be the flow fromthe anterior chamber into the suprachoroidal space.

A more complete formula is given by:

IOP=P _(e)+(F _(t) −F _(u))×R  (2)

where P_(e) and R are defined as above, F_(t) is the total outflow ofaqueous humor and F_(u) is the fraction passing via the uveoscleralroute.

IOP in human beings is normally in the range of 12-22 mm Hg. At highervalues, for instance over 22 mm Hg, there is a risk, that the eye may beaffected. In one particular form of glaucoma, low tension glaucoma,damage may occur at intraocular pressure levels otherwise regarded asphysiologically normal. The reason for this could be that the eye inthese individuals is unusually sensitive to pressure. The oppositesituation is also known, that some individuals may exhibit an abnormallyhigh intraocular pressure without any manifest defects in the visualfield or optic nerve head. Such conditions are usually referred to asocular hypertension.

Glaucoma treatments can be given by means of drugs, laser or surgery. Indrug treatment, the purpose is to lower either the flow (F) or theresistance (R) which, according to formula (1) above, will result in areduced IOP; alternatively to increase the flow via the uveoscleralroute which according to formula (2) also gives a reduced pressure.Cholinergic agonists, for instance pilocarpine, reduce the intraocularpressure mainly by increasing the outflow through Schlemm's canal.

Prostaglandins, which recently have met an increasing interest asIOP-lowering substances may be active in that they will cause anincrease in the uveoscleral outflow (Crawford et al, 1987, and Nilssonet al, 1987). They do not appear, however to have any effect on theformation of aqueous humor or on the conventional outflow throughSchlemm's canal (Crawford et al, 1987).

The use of prostaglandins and their derivatives is described forinstance in U.S. Pat. No. 4,599,353 and EP 87103714.9, and by Bito L Zet al (1983), Camras C B et al (1981, 1987a, 1987b, 1988), Giuffre G(1985), Kaufman P L (1986), Kersetter J R et al (1988), Lee P-Y et al(1988) and Villumsen J et al (1989).

With respect to the practical usefulness of some of the previouslydescribed prostaglandins and derivatives, as suitable drugs for treatingglaucoma or ocular hypertension, a limiting factor is their property ofcausing superficial irritation and vasodilation in the conjunctiva. Itis probable, moreover, that prostaglandins have an irritant effect onthe sensory nerves of the cornea. Thus local side effects will arise inthe eye already when the amounts of prostaglandin administered are quitesmall—that is, already when the doses are lower than those that would bedesirable for achieving maximum pressure reduction. It has thus beenfound, for instance, that for this reason it is clinically impossible touse PGF_(2α)-1-isopropyl ester in the amount that would give maximumpressure reduction. Prostaglandins, being naturally occurring autacoids,are very potent pharmacologically and affect both sensory nerves andsmooth muscle of the blood vessels. Since the effects caused byadministrations of PGF_(2α) and its esters to the eye, comprise inaddition to pressure reduction also irritation and hyperemia (increasedblood flow), the doses currently practicable in clinical tests arenecessarily very low. The irritation experienced when PGF_(2α) or itsesters are applied, consists mainly in a feeling of grittiness or ofhaving a foreign body in one's eye, this being usually accompanied byincreased lacrimation.

We have now found that a solution to the problems discussed above is theuse of certain derivatives of prostaglandins A, B, D, E and F. in whichthe omega chain has been modified with the common feature of containinga ring structure, for the treatment of glaucoma or ocular hypertension.

The prostaglandin derivatives have the general structure

wherein A represents the alicyclic ring C₈-C₁₂ and the bonds between thering and the side chains represent the various isomers. In PGA, PGB,PGD, PGE and PGF A has the formula

The invention is based on the use of derivatives characterized. by theiromega chain and various modifications of the alpha chain is thereforepossible still using the inventive concept. The alpha chain couldtypically be the naturally occuring alpha chain, which is esterified tothe structure

in which R₁ is an alkyl group, preferably with 1-10 carbon, especially1-6 atoms, for instance metyl, ethyl, propyl, isopropyl, butyl,isobutyl, neopentyl or benzyl or a derivative giving the final substanceequivalent properties as a glaucoma agent. The chain could preferably bea C₆-C₁₀ chain which might be saturated or unsaturated having one ormore double bonds, and allenes, or a triple bond and the chain mightcontain one or more substituents such as alkyl groups, alicyclic rings,or aromatic rings with or without hetero atoms.

The omega chain is defined by the following formula:

wherein

C is a carbon atom (the number is indicated within parenthesis)

B is a single bond, a double bond or a triple bond

D is a chain with 1-10, preferably 2-8, and especially 2-5, andparticularly 3 carbon atoms, optionally interrupted by preferably notmore than two hetero atoms (O,S, or N), the substituent on each carbonatom being H, alkyl groups, preferably lower alkyl groups within 1-5carbon atoms, a carbonyl group, or a hydroxyl group, whereby thesubstituent on C₁₅ preferably being a carbonyl group, or (R)—OH or(S)—OH; each chain D containing preferably not more than three hydroxylgroups or not more than three carbonyl groups,

R₂ is a ring structure such as a phenyl group which is unsubstituted orhas at least one substituent selected from C₁-C₅ alkyl groups, C₁-C₄alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphatic acylamino groups,nitro groups, halogen atoms, and:phenyl group; or an aromaticheterocyclic group having 5-6 ring. atoms, like thiazol, imidazole,pyrrolidine, thiophene and oxazole; or a cycloalkane or a cycloalkenewith 3-7 carbon atoms in the ring, optionally substituted with loweralkyl groups with 1-5 carbon atoms.

Some examples on derivatives which were evaluated are the following (forstructure information see Table I):

(1) 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-isopropylester

(2) 17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

(3) 15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

(4) 16-phenoxy-17,18,19,20-tetranor-PGF_(2α)-isopropylester

(5) 17-phenyl-18,19,20-trinor-PGE₂-isopropylester

(6) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGA₂-isopropylester

(7) 15-(R)-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

(8) 16-[4-(methoxy)-phenyl]-7,18,19,20-tetranor-PGF_(2α)-isopropylester

(9) 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester

(10) 18-phenyl-19,20-dinor-PGF_(2α)-isopropylester

(20) 19-phenyl-20-nor-PGF_(2α)-isopropylester

The most preferred derivatives at present are those in which the omegachain of the prostaglandin has the 18,19,20-trinor form, and especiallythe 17-phenyl analogs, such as the 15-(R)-, 15-dehydro and13,14-dihydro-17-phenyl-18,19,20-trinor forms. Such derivatives arerepresented by (3), (6), (7) and (9) in the formulas given in Table I.

In the formula given above the most preferred structure at present isaccordingly obtained when the prostaglandin is a derivative of PGA, PGD,PGE or PGF, especially of PGA₂, PGD₂, PGE₂ and PGF_(2α)

B is a single bond or a double bond

D is a carbon chain with 2-5, especially 3 atoms; C₁₅ having a carbonylor (S)—OH substituent and C₁₆-C₁₉ having lower alkyl substituents, orpreferably H

R₂ is a phenyl ring optionally having substituents selected among alkyland alkoxy groups.

The invention thus relates to the use of certain derivatives of PGA,PGB, PGD, PGE and PGF for the treatment of glaucoma or ocularhypertension. Among these derivatives defined above it has been foundthat some are irritating or otherwise not optimal, and in certain casesnot even useful due to adverse effects and these are excluded in thatthe group of prostaglandin derivatives defined above is limited totherapeutically effective and physiologically acceptable derivatives. Sois for instance (1) 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-isopropylester irritating while this can be eliminated by substituting the phenylring with a methoxy group giving formula (8) which represents atherapeutically more useful compound.

The method for treating glaucoma or ocular hypertension consists incontacting an effective intraocular pressure reducing amount of acomposition, as aforesaid, with the eye in order to reduce the eyepressure and to maintain said pressure on a reduced level. Thecomposition contains 0.1-30 μg, especially 1-10 μg, per application ofthe active substance i.e. a therapeutically active and physiologicallyacceptable derivative from the group defined above; the treatment mayadvantageously be carried out in that one drop of the composition,corresponding to about 30 μl, is administered about 1 to 2 times per dayto the patient's eye. This therapy is applicable both to human beingsand to animals.

The invention further relates to the use of therapeutically active andphysiologically acceptable prostaglandin derivatives from the groupdefined above for the preparation of an ophthalmological composition forthe treatment of glaucoma or ocular hypertension.

The prostaglandin derivative is mixed with an ophthalmologicallycompatible vehicle known per se. The vehicle which may be employed forpreparing compositions of this invention comprises aqueous solutions ase.g. physiological salines, oil solutions or ointments. The vehiclefurthermore may contain ophthalmologically compatible preservatives suchas e.g. benzalkonium chloride, surfactants like e.g. polysorbate 80,liposomes or polymers, for example methyl cellulose, polyvinyl alcohol,polyvinyl pyrrolidone and hyaluronic acid; these may be used forincreasing the viscosity. Furthermore, it is also possible to usesoluble or insoluble drug inserts when the drug is to be administered.

The invention is also related to ophthalmological compositions fortopical treatment of glaucoma or ocular hypertension which comprise aneffective intra ocular pressure reducing amount of a prostaglandinderivative as defined above and an ophthalmologically compatiblecarrier, the effective amount comprising a dose of about 0.1-30μ inabout 10-50μ of the composition.

In the experiments carried out in this investigation the activecompound, in an amount, varying with potency of the drug, from 30 μg to300 μg/ml was dissolved in a sterilized aqueous solution (saline 0.9%)containing 0.5% polysorbate-80 as solubilizing agent.

The invention is illustrated by means of the following non-limitativeexamples.

Synthesis of Prostaglandin Derivatives

EXAMPLE 1 Preparation of 16-phenyl-17,18,19,20-tetranorPGF_(2α)-isopropyl ester (1)

A 50 ml round bottom flask equipped with a magnetic stirring bar wascharged with 17.5 mg (0.04 mmol) 16-phenyl-17,18,19,20-tetranor PGF_(2α)(Cayman Chemical), 5 ml CH₂Cl₂, 30.2 mg (0.23 mmol)diisopropylethylamine. This solution was stirred at −10° C. and 13.5 mg(0.07 mmol) of isopropyltriflate (freshly prepared) was added. Thissolution was allowed to stand at −10° C. for 15 min and was then slowlywarmed to room temperature. When the esterification was completeaccording to TLC (usually after 3-4 h at room temperature) the solventwas removed in vacuo. The residue was diluted with 20 ml ethylacetate,washed with 2×10 ml 5% sodium hydrogencarbonate and 2×10 ml 3% citricacid. The organic layer was dried over unhydrous sodium sulfate. Thesolvent was removed in vacuo and the residue was purified by columnchromatography on silica gel-60 using ethyl acetate: aceton 2: 1 aseluent. The title compound was obtained as a colourless oily substance(71% yield).

Nuclear Magnetic Resonance spectrum (CDCl₃)— ppm: δ  1.2 (6H d) 3.3 (1Hq) 2.85 (2H d) 5.0 (1H m) 3.85 (1H m) 5.3-5.7 (4H m) 4.15 (1H t)7.15-7.35 (5H m)

EXAMPLE 2 Preparation of 17-phenyl-18,19,20-trinor PGF_(2α)-isopropylester (2)

A 50 ml round bottom flask equipped with a magnetic stirring bar wascharged with 20mg (0.05 mmol) 17-phenyl-18,19,20-trinor PGF_(2α) (CaymanChemicals), 6 ml acetone, 39.2 mg (0.25 mmol) DBU and 42.5 mg (0.25mmol) isopropyl iodide. The solution was allowed to stand at roomtemperature for 24 h, the solvent was removed in vacuo and the residuewas diluted with 30 ml of ethyl acetate, washed twice with 10 ml 5%sodiumhydrogen carbonate and 10 ml 3% citric acid. The solvent wasremoved in vacuo, and the crude product was chromatographed on silicagel-60 using ethyl acetate: acetone 2:1 as eluent. The title compound(2) was obtained as an oily substance (65% yield).

Nuclear Magnetic Resonance spectrum (CDCl₃)— ppm: δ 1.2 (6 m) 4.9 (1H m)3.9 (1H m) 5.4-5.6 (4H m) 4.1 (1H t) 7.1-7.3 (5H m) 4.2 (1H m)

EXAMPLE 3 Preparation of 15-dehydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl ester (3)

20.9 mg (0.092 mmol) DDQ was added to a solution of 10 mg (0.023 mmol)17-phenyl-18,19,20 trinor PGF_(2α) isopropyl ester (2) in 8 ml dioxane.The reaction mixture immediately turned brown, the reaction mixture wasstirred at room temperature for 24 h. The precipitate formed wasfiltered, washed with 10 ml ethyl acetate, the filtrate was diluted with10 ml ethylacetate washed with 2×10 ml water, 2×10 ml NaOH IM and 20 mlbrine. The organic layer was dried on unhydrous sodium sulfate and thesolvent was removed in vacuo, the residue was purified by columnchromatography on silica gel using ethyl acetate: ether 1:1 as eluent.The title compound (3) was obtained as a colourless oily substance (76%yield).

Nuclear Magnetic Resonance spectrum (CDCl₃),— ppm: δ 1.2 (6H d) 5.4 (2Hm) 4.0 (1H m) 6.2 (1H d) 4.2 (1H m) 6.7 (1H q) 5.0 (1H m) 7.15-7.35 (5Hm)

EXAMPLE 4 Preparation of 16-phenoxy-17,18,19,20 -tetranorPGF_(2α)-isopropyl ester(4)

Following a procedure similar to that described in example 2 using 20 mg(0.051 mmol) 16-phenoxy-17,18,19,20 -tetranor PGF_(2α) (CaymanChemicals). The title compound (4) was an oily substance (53.2% yield).

Nuclear Magnetic Resonance spectrum (CDCl₃)— ppm: δ 1.2 (6H d) 5.4 (2Hm) 3.9 (3H m) 5.7 (2H m) 4.2 (1H m) 6.9 (3H m) 4.5 (1H m) 7.3 (2H m) 5.0(1H m)

EXAMPLE 5 Preparation of 17-phenyl-18,19,20-trinor PGE_(2α)-isopropylester (5)

Following a procedure similar to that described in example 2 using 10 mg(0.026 mmol) 17-phenyl-18,19,20-trinor PGE_(2α) (Cayman Chemicals). Thecrude product was purified by column chromatography on silica gel-60using ether as eluent. The title compound (5) was an oily substance(38.9% yield).

Nuclear Magnetic Resonance spectrum (CDCl₃)— ppm: δ 1.2 (6H d) 5.3 (2Hm) 3.9-4.1 (2H m) 5.6 (2H m) 4.9 (1H m) 7.2 (5H m)

EXAMPLE 6 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinorPGA_(2α)-isopropyl ester (6)

Following a procedure similar to that described in example 2 using 10 mg(0.026 mmol) 13,14-dihydro-17-phenyl PGA_(2α) (Cayman Chemicals). Thecrude product was chromatographed on silica gel-60 using ether aseluent.

Nuclear Magnetic Resonance spectrum (CDCl₃)— ppm: δ 1.2 (6H d) 5.4 (2Hm) 4.35 (1H m) 7.3 (5H m) 5.0 (1H m)

EXAMPLE 7 Preparation of 15-(R)-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl ester (7). (Table II) 7.1 Preparation of1-(S)-2-oxa-3-oxo-6-(R)-(3-oxo-5-phenyl-1-trans-pentenyl)-7-(R)-(4-phenylbenzoyloxy)-cis-bicyclo[3,3,0]octane (13)

18 g (0.05 mol) alcohol (11), 32 g (0.15 mol) DCC, 39.1 g (0.5 mol) DMSO(newly distilled from CaH₂) and 30 ml DME were charged to a 200 ml flaskunder nitrogen. Orthophosphoric acid was added in one portion, and anexothermic reaction occured. The reaction mixture was stirredmechanically at room temperature for 2 h, and the resultant precipitatewas filtered and washed with DME. The filtrate (12) can be used directlyfor Emmon condensation reaction.

To a suspension of 1.2 g (0.04 mol) NaH (80% washed with n-pentane toremove mineral oil) in 100 ml DME under nitrogen was added dropwise 12.3g (0.048) dimethyl-2-oxo-4-phenyl-butyl-phosphonate in 30 ml DME. Themixture was stirred mechanically for Ih at room temperature, then cooledto −10° C. and a solution of the crude aldehyde (12) was added indropwise. After 15 min at 0° C. and 1 h at room temperature the reactionmixture was neutralized with glacial acetic acid, the solvent wasremoved under vaccum, and to the residue was added 100 ml ethyl acetate,washed with 50 ml water and 50 ml brine. The organic layer was driedover unhydrous sodium sulfate. The solvent was removed in vacuo and theresulting white precipitate filtered and washed with cold ether. Thetitle compound (13) was obtained as a crystalline substance mp134.5-135.5 (53% yield).

7.2 Preparation of1-(S)-2-oxa-3oxo-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-(4-phenylbenzoyloxy)cis-bicyclo[3,3,0]octane (14)

10 g (0.021 mol) enone (13) and 3.1 g (0,008 mol) cerouschlorideheptahydrate in 50 ml methanol and 2 ml CH₂Cl₂ were charged to a 200 mlround bottom flask equipped with a magnetic stirring bar and was cooledto −78° C. under nitrogen: Sodium borohydride was added in smallportions, after 30 min the reaction mixture was quenched by addition ofsaturuted NH₄Cl, and extracted with 2×50 ml ethyl acetate. The extractsswere dried and concentrated to leave a colourless oil (98% yield).

7.3 Preparation of1-(S)-2-oxa-3-oxo-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo-[3,3,0]octane(15)

To a solution of 9.8 g (0.02 mol) ketal (14) in 100 ml absolute methanolwas added 1.7 (0.012 mol) potassium carbonate. The mixture was stirredwith a magnetic bar, at room temperature after 3 h. The mixture wasneutralized with 40 ml HCl 1 M, and extracted with 2×50 ml ethylacetate. The extracts were then dried on unhydrous sodium sulfate andconcentrated. The crude product was chromatographed on silica gel usingethyl acetate: acetone as eluent. The title compound (15) was obtainedas an oily substance (85% yield).

7.4 Preparation of1-(S)-2-oxa-3-hydroxy-6-(R)-[3-(R,S)-hydroxy-4-phenyl-1-trans-pentenyl]-7-(R)-hydroxy-cis-bicyclo[3,3,0](16)

To a solution of 3 g (0.011 mol) lactone (15) in 60 ml unhydrous THF,stirred magnetically and cooled to −78° C., 4.5 g (0.0315 mol) DIBAL-Hin toluene was added dropwise. After 2 h the reaction mixture wasquenched by addition of 75 ml methanol. The mixture was filtered,thefiltrate was concentrated in vacuo and the residue was chromatographedon silica gel-60 using ethyl acetate: acetone 1:1 as eluent. The titlecompound (16) was obtained as a semisolid substance (78% yield).

7.5 Preparation of 15-(R,S)-17-phenyl-18,19,20-trinor PGF_(2α)(17)

2.5 g (25 mmol) sodium methyl sulfinylmethide in DMSO (freshly preparedfrom sodium anhydride and DMSO) was added dropwise to a solution of 5.6g (12.6 mmol) 4-caboxybutyl triphenyl-phosphonium bromide in 12 ml DMSO.To the resultant red solution of the ylide was added dropwise a solutionof the 1.2 g (4.2 mmol) hemiacetal (16) in 13 ml DMSO, and the mixturewas stirred for 1 h. The reaction mixture was diluted with 10 g ice and10 ml water and extracted with 2×50 ml ethyl acetate, whereafter theaqueous layer was cooled, acidified with HCl 1 M and extracted withethyl acetate, and then the organic layer was dried and concentrated.The resulting crude product was a colourless substance. The purity ofthe title compound (17) was estimated by TLC on silica gel using ethylacetate: acetone: acetic acid 1:1:0.2 v/v/v as eluent.

7.6 Preparation of 15-(R)-17-phenyl-18,19,20-trinor PGF_(2α)-isopropylester (7)

The crude product (17) was esterified following a procedure similar tothat described in example 2 the product was purified by columnchromatography on silica gel-60 using ethyl acetate as eluent and theresulting mixture of C₁₅ epimeric alcohol were separated.

The title compound (7) was obtained as a colourless oily substance (46.tyield).

Nuclear Magnetic Resonance spectrum (CDCl₃),— ppm: δ 1.2 (6H m) 5.4 (2Hm) 3.9 (1H m) 5.6 (2H m) 4.15 (2H m) 7.2 (5H m) 4.95 (1H m)

EXAMPLE 8 Preparation of 16-[4-(methoxy)phenyl]-17,18,19,20-tetranorPGF_(2α)-isopropyl ester (8)

Following a procedure similar to that described in example 7 withmodified step 7-2, the aldehyde 12 described in step 7-2 was reactedwith dimethyl-2-oxo-3-[4-(methoxy)phenyl]-propylphosphonate and waspurified by column chromatography on silica gel-60 using ethyl acetate:toluene 1:1 as eluent. A colourless oily substance was obtained (57%yield).

The title compound 16-[4-(methoxy)phenyl]-17,18,19,20-tetranorPGF_(2α)-isopropyl ester (8) was obtained as an oily substance, andpurified by column chromatography on silica gel-60 using ethyl acetateas eluent (46% yield).

Nuclear Magnetic Resonance spectrwu (CDCl₃)— ppm: δ 1.2 (6H d) 5.0 (1Hm) 2.8 (2H d) 5.4 (2H m) 3.75 (3H S) 5.6 (2H m) 3.9 (1H m) 6.8 (2H d)4.15 (1H m) 7.2 (2H d) 4.3 (1H m)

EXAMPLE 9 Preparation of 13,14-dihydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl ester (9)

Following a procedure similar to that described in example 7, with minormodification, 5 g (0.018 mol) enone (13) in 100 ml THF was reducedusing: 2.03 g 10% pd/c under hydrogen atmosphere. After completion ofthe: reaction (as determined by TLC on silica gel using ethylacetate:toluene 1:1 as eluent) the mixture was filtered on celite. The filtratewas concentrated in vacuo and an oily substance was obtained (86%yield).

The final product 13,14-dihydro-17-phenyl-18,19,20-trinorPGF_(2α)-isopropyl aster containing a mixture of C₁₅ epimeric alcoholswere separated by preparative liquid chromatography using 40% CH₃CN inwater v/v as eluent.

Nuclear Magnetic Renonance spectrum (CDCl₃)— ppm: δ 1.2 (6H d) 5.0 (1Hm) 3.6 (1H m) 5.4 (2H m) 3.9 (1H m) 7.2 (5H m) 4.15 (1H m)

EXAMPLE 10 Preparation of 18-phenyl-19,20-trinor PGF_(2α)-isopropylester (10)

Following a procedure similar to that described in example (7) withmodified step 7-2. The aldehyde (12) described in 7-2 was reacted withdimethyl-2-oxo-5-phenyl pentyl phosphonate gave a crystalline substancetrans-enone lactone (67% yield).

The final product 18-phenyl-19,20-dinor PGF_(2α)-isopropyl ester (10)was purified by column chromatography on silica gel-60 using ethylacetate as eluent gave a colourless oil (41% yield).

1.2 (6H d) 5.0 (1H m) 3.95 (1H m) 5.4 (2H m) 4.10 (1H m) 5.6 (2H q) 4.20(1H m) 7.2 (5H m)

EXAMPLE 11 Preparation of 19-phenyl-20-nor-PGF_(2α)-isopropyl ester (20)

Following a procedure similar to that described in example (7) withmodified step (7-2).

The aldehyde (12) described in (7-2) was reacted withdimethyl-2-oxo-6-phenyl-hexylphosphonate gave a colourless oiltrans-enone lactone (56% yield).

The final product 19-phenyl-20-nor-PGF_(2α)-isopropyl ester (20) was acolourless oil, and was purified by column chromatography on silicagel-60 using ethyl acetate as eluent (30% yield).

Nuclear Magnetic Resonance spectrum (CDCl₃)-ppm: δ 1.2 (6H d) 5.0 (1H m)2.6 (2H t) 5.4 (2H m) 3.9 (1H m) 5.5 (2H t) 4.1 (1H m) 7.2 (5H m) 4.2(1H m)

Studies of Eye Pressure Lowering Effect and Adverse Reactions

The intraocular pressure (IOP) was determined in animals with apneumatonometer (Digilab Modular One™, Bio Rad), specially calibratedfor the eye of the particular species. The cornea was anaesthetized with1-2 drops of oxibuprocain before each IOP measurement. In healthy humanvolunteers IOP was measured with applanation tonometry or with an airpuff tonometer (Keeler pulsair). For applanation tonometry either apneumatonometer (Digilab) or Goldmann's applanation tonometer mounted ona slit lamp microscope was used. The cornea was anaesthetized withoxibuprocain before each measurement with applanation tonometry. Nolocal anaesthesia was employed before measurement with the pulsairtonometer.

The ocular discomfort after application of the test substances wasevaluated in cats. The behaviour of cats after topical application ofthe test drug was followed and ocular discomfort was graded on a scalefrom 0 to 3, 0 indicating complete absence of any signs of discomfort,and 3 indicating maximal irritation as obvious from complete lidclosure.

Conjunctival hyperemia after topical application of the test substanceswas evaluated in rabbits. The conjunctiva at the insertion of thesuperior rectus muscle of the eye was inspected or photographed withregular intervals and the degree of hyperemia was later evaluated fromthe color photographs in a blind manner. Conjunctival hyperemia wasevaluated on a scale from 0 to 4, 0 indicating complete absence of anyhyperemia, and 4 indicating marked hyperemia with conjunctival chemosis.

For determination of the effects on the intraocular pressure, primarilymonkeys (cynomolgus) were employed. The reason for this is that themonkey eye is highly reminiscent of the human eye and therefor,generally, drug effects are readily extrapolated to the human eye.However, the disadvantage of using the monkey eye as a model is that theconjunctiva in this species is pigmented making it impossible toevaluate conjunctival hyperemia and furthermore, the monkey eye isrelatively insensitive to irritation. Therefore, the cat eye, being verysensitive to prostaglandins was used for evaluating ocular discomfortand the rabbit eye with pronounced tendency to hyperemic reactions wasused for evaluating conjunctival and episcleral hyperemia.

It is evident from Table III that modification of the omega chain of theprostaglandin skeleton introduced new and unexpected features to theprostaglandins with respect to ocular irritation (discomfort).Particularly 17-phenyl,18,19,20-trinor-PGF_(2α)-IE and analogs we reunique in exhibiting a completeloss of ocular Irritation with retainedIOP lowering effect in monkeys. Whereas the17phenyl,18,19,2trirnor-PGF_(2α) derivatives were extremely welltolerated, 16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IE caused clearocular discomfort although to a lesser degree than PGF_(2α)-IE or15-propionate-PGE₂-IE (Table III). However, substituting a hydrogen atomin the phenyl ring with a methoxy group having electron donatingproperties rendered the molecule practically free of ocular irritatingeffect, Table III. It is also evident from Table III that18-phenyl-19,20,-dinor-PGF_(2α)EI, 19-phenyl-20-nor-PGF_(2α)-IE as wellas 17-phenyl-18,19,20-trinor-PGE₂-IE and13,14-dihydro-17-phenyl-18,19,20-trinor-PGA_(2α)-IE, had no or verylittle irritating effect In the eye of cats. This indicates that theinvention not only is valid for 16-, and 17-tetra- and trinor analogs ofPGF_(2α) but for a range of omega chain modified and ring substitutedanalogs of PGF_(2α) (as exemplified with16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IE to19-phenyl-20-nor-PGF_(2α)-IE), and more importantly even for differentmembers of the prostaglandin family such as PGE₂ and PGA₂ modified in ananalogous way (Table III). Thus, modifying the omega chain andsubstituting a carbon atom in the chain with a ring structure introducescompletely new, unexpected and advantageous qualities to naturallyoccuring prostaglandins in that the irritating effect in the conjunctivaand cornea is abolished. In the case of16-phenyl-17,18,19,20-tetranor-PGF_(2α)-IE exhibiting some irritatingeffect substituting a hydrogen atom in the ring structure with e.g. amethoxy group attenuates or abolishes the irritating effect.

In addition to the lack of ocular discomfort the omega chain modifiedanalogs also exhibited an advantage over naturally occuringprostalgandins in that they caused considerably less conjunctivalhyperemia as studied in the rabbit eye (Table IV). Particularly,15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,and 13,14-dihydro-17-phenyl-18,19,20-trinor PGA₂-IE were advantageous inthis respect. Also 18-phenyl-19,20-dinor-PGF_(2α)-IE and19-phenyl-20-nor-PGF_(2α)-IE induced very little conjunctival hyperemia(TableIV).

The intraocular pressure lowering effect of omega chain modified andring-substituted prostaglandin analogs is demonstrated in Table V. Itcan be seen that particularly 16-phenyl-tetranor and 17-phenyl-trinorprostaglandin analogs significantly reduced IOP in animal eyes (TableV). In all but two series of experiments cynomolgus monkeys were used.It is of particular interest to note that 17-phenyl-18,19,20-trinorPGF_(2α)-derivatives exhibiting no ocular irritation and only modestconjunctival/episcleral hyperemia significantly lowered IOP in primates.It should furthermore be observed that both16-phenyl-17,18,19,20-tetranor-PGF₆₀ -IE,18-phenyl-19,20-dinor-PGF_(2α)-IE and 19-phenyl-20-nor-PGF₆₀ -IE reducedthe intraocular pressure, thus, modification of the omega chain andsubstituting a carbon atom in the chain with a ring structure do notrender the molecule inactive with respect to the effect on theintraocular pressure.

Furthermore, it should be observed that substituting a hydrogen on thering structure of 16-phenyl,17,18,19,20-tetranor-PGF_(2α)-IE with amethoxy group eliminated much of the ocular irritating effect preservingmost of the intraocular pressure lowering effect. Thus, omega chainmodified and ring substituted prostaglandin analogs reduce IOPeffectively in animals. It is further demonstrated in Table V that16-phenoxy-17,18,19,10-etranor-PGF_(2α)-IE effectively lowers theintraocular pressure as studied in cats. Thus, substituting carbon 17 inthe omega chain with a hetero atom, in this case oxygen, does not renderthe molecule inactive with respect to the effect on IOP.

It is noteworthy that most of the17-phenyl,18,19,20-trinor-prostaglandin analogs had poor intraocularpressure lowering effect in cats, even at high doses. It is to beobserved that the doses at which compounds were used presented in TableIII are lower than those e.g. in Table V. Doses presented in Table IIIshould be explicitly compared with those of the naturally occuringprostaglandins in the same table. The same is true for Table IV. It isclear that with increasing dose side effects may increase. However, thedoses of prostaglandin derivatives used in monkeys are comparativelysimilar to those used in human volunteers, (Table VI) being practicallyfree of side effects.

The effect of some omega chain modified prostaglandin analogs, morespecifically 17-phenyl-18,19,20-trinor-PGF_(2α)-IE,15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,15-(R)-17-phenyl-18,19,20-trinor-PGF_(2α)-IE,13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE, and18-phenyl-19-20-dinor-PGF_(2α)-IE on the intraocular pressure of healthyhuman volunteers is demonstrated in Table VI. All compoundssignificantly reduced the intraocular pressure. It is particularlysignificant in this respect that none of the compounds had anysignificant irritating effect (ocular discomfort) and that13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE and15-dehydro-17-phenyl-18,19,20-trinor-PGF_(2α)-IE caused very little ifany conjunctival/episcleral hyperemia in man. Thus, omega chainmodified, and ring substituted prostaglandin analogs seem to be uniquein that these compounds reduce IOP without causing significant. ocularside effects such as hyperemia and discomfort.

The present invention thus describes a group of compounds exhibiting theunique property of causing insignificant ocular side effects whileretaining the intraocular pressure lowering effect. From the foregoingit is evident that the crucial modification of the molecule is a ringstructure in the omega chain. Furthermore, substituents in the ringstructure and/or in the omega chain may be introduced in certainmolecules still exhibiting some side-effects in the eye. Hetero atomsmay also be introduced into the ring substituted omega chain. Presently,particularly 17-phenyl-18,19,20-trinor-PGF_(2α)-derivatives seem verypromising for therapeutic use in glaucoma. From the scientificliterature it is evident that PGE₂ and PGA₂ or their esters lower IOP inthe monkey (see Bito et al, 1989). Clinical studies with PGE₂ have alsobeen performed demonstrating IOP-lowering effect in man (Flach andEliason (1988)). Thus, the analogy with PGF_(2α) and its esters loweringIOP in the primate eye is logic. It is most reasonable to assume thatother prostaglandins with modified omega chain exhibit essentially thesame properties as PGF_(2α) with modified omega chain, i.e. IOP loweringeffect without side effects.

TABLE I

TABLE II

Reagents: a) DCC/DMSO/DME b) NaH/dimethyl-2-oxo-4-phenylbutylphosphonate/DME c) CeCl₃.7H₂O/NaBH₄/CH₃ ⁻OH/−78° C. d) K₂CO₃/CH₃OH e)Dibal/−78° C. f) NaCH₂SOCH₃/(4-carboxybutyl)-triphenylphosphoniumbromide/DMSO g) DBU/iprI/acetate

TABLE III Irritative effect of naturally occuring prosta- glandins(PGF_(2α), PGD₂ and PGE₂), and omega chain modified analogs applied asisopropylester on the cat eye. The avarage degree of discomfort wasevaluated during 60 min after topical application of the respective testdrug. The numbers within paranthesis refer to Table I. Dose Degree ofSubstance (pg) occular irritation PGF_(2α)-isopropylester (-IE) 1 3.0 ±0.0 15-propionate-PGE₂-IE 0.1-1   3.0 ± 0.0 15-propionate-PGD₂-IE 1 1.3± 0.2 17-phenyl-18,19,20- (2) 1-5 0 trinor-PGF_(2α)-IE15-dehydro-17-phenyl- (3) 5 0 18,19,20-trinor- PGF_(2α)-IE15-(R)-17-phenyl- (7) 1-5 0 18,19,20-trinor-PGF_(2α)-IE13.14-dihydro-17-phenyl- (9) 1 0 18,19,20-trinor-PGF_(2α)-IE17-phenyl-18,19,20- (5) 0.3 0 trinor-PGE₂-IE 13,14-dihydro-17-phenyl-(6) 1 0 18,19,20-trinor-PGA₂-IE 16-phenyl-17,18,19,20- (1) 1 2.2 ± 0.3tetranor-PGF_(2α)-IE 16-[4-(methoxy)-phenyl] (8) 1 0.2 ± 0.117,18,19,20-tetranor- PGF_(2α)-IE 18-phenyl-19,20-dinor- (10) 1 0.7 ±0.1 PGF_(2α)-IE 19-phenyl-20-nor-PGF_(2α)-IE (20) 1 0.5 ± 0.116-phenoxy-17,18,19,20- (4) 5 0.3 ± 0.2 tetranor-PGF_(2α)-IE

TABLE IV Degree of conjunctival hyperemia in the rabbit eye afterapplication of naturally occuring prostaglandins (PGF_(2α), and PGE₂),and omega chain modified analogs applied as isopropylesters. Dose Degreeof Substance (pg) hyperemia PGF_(2α)-isopropylester (-IE) 0.1 2.8 ± 0.215-propionate-PGE₂-IE 0.5 2.7 ± 0.3 16-phenyl-17,18,19,20- (1) 0.5 1.3 ±0.9 tetranor-PGF_(2α)-IE 17-phenyl-18,19,20-trinor- (2) 0.5 2.0 ± 0.3PGF_(2α)-IE 15-dehydro-17-phenyl- (3) 0.5 0.7 ± 0.318,19,20-trinor-PGF_(2α)-IE 15-(R)-17-phenyl-18,19,20- (7) 0.5 2.0 ± 0.0trinor-PGF_(2α)-IE 13,14-dihydro-17-phenyl- (9) 0.5 1.3 ± 0.318,19,20-trinor-PGF_(2α)-IE 17-phenyl-18,19,20-trinor- (5) 0.5 2.7 ± 0.2PGE₂-IE 13,14-dihydro-17-phenyl (6) 0.5 0.3 ± 0.318,19,20-trinor-PGA₂-IE 18-phenyl-19,20-dinor- (10) 0.5 0.3 ± 0.2PGF_(2α)-IE 19-phenyl-20-nor-PGF_(2α)-IE (20) 0.5 0.2 ± 0.216-phenoxy-17,18,19,20- (4) 0.5 2.3 ± 0.3 tetranor-PGF_(2α)-IE

TABLE V Intraocular pressure reducing effect of naturally occuringprostaglandin (PGF_(2α)) and omega chain modified analogs as determinedin cynomolgus monkeys or cats. Unless specified data were obtained inmonkeys. The figures within parenthesis refer to formulas given in TableI. Time after administration (hours)  0 1-2 3-4 6 Substance Dose (μg) (mmHg) (mmHg) (mmHg) (mmHg) PGF_(2α)-isopropylester (IE)  1.5 E 11.4 ±0.7  8.3 ± 0.5*  8.0 ± 0.6*  9.3 ± 0.8 C 11.0 ± 0.7 10.7 ± 0.4 10.1 ±0.4 10.6 ± 0.9 16-phenyl-17,18,19,20-  3.2 E 12.7 ± 1.1 11.8 ± 1.1  9.1± 0.8*  8.4 ± 0.7* tetranor-PGF_(2α)-IE (1) C 12.8 ± 0.5 14.0 ± 0.2 13.0± 0.8 11.7 ± 0.8 17-phenyl-18,19,20-  3.2 E 12.8 ± 0.6 11.9 ± 0.5  8.6 ±0.3*  9.5 ± 0.7 trinor-PGF_(2α)-IE (2) C 13.4 ± 0.6 11.7 ± 0.6 12.4 ±0.2 11.9 ± 0.7 13,14-dihydro-17-phenyl- 10.4 E 11.1 ± 0.9  8.3 ± 0.6 6.9 ± 0.4*  7.7 ± 0.8 18,19,20-trinor-PGF_(2α)-IE (9) C 10.6 ± 0.7  8.8± 0.9 10.3 ± 1.1  9.5 ± 1.0 18-phenyl-19,20-dinor-  3.1 E  9.7 ± 0.9 9.6 ± 1.1  9.6 ± 0.7  8.8 ± 0.9 PGF_(2α)-IE (10) C 10.1 ± 1.0  9.4 ±1.2  9.8 ± 1.2  9.4 ± 0.9 16-phenoxy-17,18,19,20-  5** E 20.5 ± 1.2 25.7± 1.2 19.2 ± 1.8  15.0 ± 1.2* tetranor-PGF_(2α)-IE (4) C 20.7 ± 1.2 22.7± 1.1 19.5 ± 0.9 19.2 ± 0.8 16-[4-(methoxy)-phenyl]-  3.2 E 11.2 ± 0.910.5 ± 1.3  9.8 ± 1.4*  9.2 ± 0.9 17,18,19,20-tetranor- C 10.4 ± 1.110.9 ± 1.0 11.3 ± 1.4  9.2 ± 0.6 PGF_(2α)-IE (8) 19-phenyl-20-nor-  1**E 16.9 ± 1.0 16.6 ± 0.7  15.8 ± 0.8* 18.1 ± 1.2 PGF_(2α)-IE (20) C 17.1± 0.4 18.1 ± 0.6 18.9 ± 0.6 19.2 ± 0.8 *Indicates statisticalsignificance p < 0.05. The substances were applied topically. **Dataobtained in cat eyes.

TABLE VI Intraocular pressure reducing effect of different omega chainmodified and ring substituted PGF_(2α)-IE analogs in healthy humanvolunteers. The substance number is given within paranthesis. Time afteradministration (hours) Dose 0 4 6 8 Substance (μg) n Eye (mmHg) (mmHg)(mmHg) (mmHg) 17-phenyl-18,19,20-trinor- 1 4 Exp 11.9 ± 1.7  11.0 ± 0.9* 10.1 ± 0.7*  9.8 ± 0.7* PGF_(2α)-isopropylester (IE) (2) Contr 12.7 ±1.7 13.9 ± 0.7 13.5 ± 1.2 12.5 ± 0.7 15-(R)-17-phenyl-18,19,20- 10  3Exp 12.9 ± 0.9 11.8 ± 0.6 11.0 ± 0.3  11.2 ± 1.3* trinor-PGF_(2α)-IE (7)Contr 13.2 ± 1.4 13.7 ± 0.9 13.8 ± 1.0 15.1 ± 1.3 15-dehydro-17-phenyl-10  4 Exp 17.7 ± 0.6  14.6 ± 0.2*  13.6 ± 0.7* —18,19,20-trinor-PGF_(2α)-IE (e) Contr 17.5 ± 0.7 16.4 ± 0.5 16.3 ± 1.0 —13,14-dihydro-17-phenyl- 1 4 Exp 14.2 ± 0.5 13.3 ± 1.1  12.2 ± 0.4* 12.5± 0.9 18,19,20-trinor-PGF_(2α)-IE (9) Contr 13.5 ± 0.6 14.2 ± 1.2 15.2 ±1.0 15.1 ± 0.7 18-phenyl-19,20-dinor- 5 3 Exp 14.4 ± 1.0 12.2 ± 1.1 12.4± 1.2  11.9 ± 0.7* PGF_(2α)-IE (10) Contr 15.2 ± 0.1 13.7 ± 1.2 14.4 ±0.2 13.2 ± 0.5 *Indicates statistical significance p < 0.05.

REFERENCES

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Bito L Z, Camras C B, Gum G G and Resul B (1989). The ocular hypotensiveeffects and side effects of prostaglandins on the eyes of experimentalanimals. Progress in clinical and biological research, Vol 312. EdLaszlo Z Bito and Johan Stjernschantz; Alan R Liss, Inc., New York.

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What is claimed is:
 1. A therapeutic composition for topical treatmentof glaucoma or ocular hypertension in humans containing a prostaglandinPGA, PGB, PGE or PGF in an amount sufficient to reduce intraocularpressure without causing substantial ocular irritation and anophthalmologically compatible vehicle, wherein the omega chain of theprostaglandin has the formula C₁₃—B—C₁₄—D—R₂ wherein C is a carbon atom(the number according to standard prostaglandin nomenclature beingindicated by the subscript); B is a single bond or double bond; D is asubchain of 3 carbon atoms, having a hydroxyl group substituent; and R₂is 17-phenyl which is urnsubstituted or has at least one substituentselected from the group consisting of C₁-C₅ alkyl groups, C₁-C₄ alkoxygroups, trifluoromethyl groups, C₁-C₃ aliphatic acylamino groups, nitrogroups, and a phenyl group.
 2. A method of treating glaucoma or ocularhypertension in humans by topical application of a therapeuticcomposition according to claim
 1. 3. The therapeutic composition ofclaim 1, wherein B is a single bond.
 4. The therapeutic composition ofclaim 1, wherein B is a double bond.
 5. The therapeutic composition ofclaim 1, wherein R₂ is an unsubstituted 17-phenyl group.
 6. Thetherapeutic composition of claim 1, wherein R₂ is a 17-phenyl grouphaving at least one substituent selected from the group consisting ofC₁-C₅ alkyl groups, C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃aliphatic acylamino groups, nitro groups, and a phenyl group.
 7. Thetherapeutic composition of claim 1, wherein the prostaglandin is a PGFprostaglandin.
 8. The therapeutic composition of claim 1, wherein saidhydroxyl group substituent is on the C₁₅ atom of the D subchain.
 9. Thetherapeutic composition of claim 8, wherein R₂ is an unsubstituted17-phenyl group.
 10. The therapeutic composition of claim 8, wherein theprostaglandin is a PGF prostaglandin, the hydroxyl group substituent onthe C₁₅ atom of the D subchain is a 15-(R) hydroxy substituent, and R₂is an unsubstituted 17-phenyl group.
 11. The therapeutic composition ofclaim 1, wherein said prostaglandin is17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester.
 12. The therapeuticcomposition of claim 1, wherein said prostaglandin is15-(R)-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester.
 13. Thetherapeutic composition of claim 1, wherein said prostaglandin is13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropylester.
 14. Thetherapeutic composition of claim 1, wherein said prostaglandin is15-(R,S)-17-phenyl-18,19,20-trinor-PGF_(2α).
 15. A therapeuticcomposition for topical treatment of glaucoma or ocular hypertension inhumans containing a prostaglandin PGA, PGB, PGE or PGF in an amountsufficient to reduce intraocular pressure without causing substantialocular irritation and an ophthalmologically compatible vehicle, whereinthe omega chain of the prostaglandin has the formula C₁₃—B—C₁₄—D—R₂wherein C is a carbon atom (the number according to standardprostaglandin nomenclature being indicated by the subscript); B is asingle bond or double bond; D is a subchain of 2-5 carbon atoms, with asubstituent at C₁₅ selected from the group consisting of hydroxyl andoxo; and R₂ is a terminal phenyl group which is unsubstituted or has atleast one substituent selected from the group consisting of C₁-C₅ alkylgroups, C₁-C₄ alkoxy groups, trifluoromethyl groups, C₁-C₃ aliphaticacylamino groups, nitro groups, and a phenyl group.
 16. A method oftreating glaucoma or ocular hypertension in humans by topicalapplication of a therapeutic composition according to claim
 15. 17. Thetherapeutic composition of claim 15, wherein B is a single bond.
 18. Thetherapeutic composition of claim 15, wherein B is a double bond.
 19. Thetherapeutic composition of claim 15, wherein D is a subchain of 3 carbonatoms and R₂ is an unsubstituted 17-phenyl group.
 20. The therapeuticcomposition of claim 15 wherein the substituent at C₁₅ is hydroxyl. 21.The therapeutic composition of claim 15 wherein the substituent at C₁₅is oxo.
 22. The therapeutic composition of claim 19 wherein thesubstituent at C₁₅ is hydroxyl.
 23. The therapeutic composition of claim19 wherein the substituent at C₁₅ is oxo.
 24. The therapeuticcomposition of claim 15, wherein D is a subchain of 3 carbon atoms andR₂ is a phenyl group having at least one substituent selected from thegroup consisting of C₁-C₅ alkyl groups, C₁-C₄ alkoxy groups,trifluoromethyl groups, C₁-C₃ aliphatic acylamino groups, nitro groups,and a phenyl group.
 25. The therapeutic composition of claim 15, whereinthe prostaglandin is a PGF prostaglandin.
 26. The therapeuticcomposition of claim 1, wherein said prostaglandin is15-(R)-13,14-dihydro-17-phenyl-18,19,20-trinor-PGF_(2α)-isopropyl ester.27. The therapeutic composition of claim 8, wherein the prostaglandin isa PGF prostaglandin, the hydroxyl group substituent on the C₁₅ atom ofthe D subchain is a 15-(S) hydroxy substituent, and R₂ is anunsubstituted 17-phenyl group.
 28. The therapeutic composition of claim9, wherein the prostaglandin is a PGF₆₀ prostaglandin and B is a doublebond.
 29. A therapeutic composition for topical treatment of glaucoma orocular hypertension in humans containing a PGF_(2α) prostaglandin in anamount sufficient to reduce intraocular pressure without causingsubstantial ocular irritation and an ophthalmologically compatiblevehicle, wherein the omega chain of the prostaglandin has the formulaC₁₃—B—C₁₄—D—R₂ wherein C is a carbon atom (the number according tostandard prostaglandin nomenclature being indicated by the subscript); Bis a double bond; D is a subchain of 3 carbon atoms, having a hydroxylgroup substituent on the C₁₅ atom of the D subchain; and R₂ is anunsubstituted 17-phenyl group.